Organ Failure due to Systemic Injury in Acute Pancreatitis

Specific therapy for Organ Failure:
Since the systemic injury is a result of dysregulated and out of proportion systemic 
inflammation in response to the local injury, specific treatment aimed at putative critical 
pathways has been tried. As mentioned above, PAF antagonist, Lexipafant, failed in a 
randomized controlled trial (RCT) involving 290 patients with predicted severe AP having 
an APACHE II score of >6. However, the treatment failed to provide any therapeutic benefit 
mainly because the primary hypothesis was invalidated by the unexpected finding that 44% 
of patients had OF on entry and only 14% patients developed new OF.
150
Intravenous 
antioxidants too failed in a RCT of 43 patients, the primary endpoint i.e. OF developed in 
32% and 17% in antioxidant and placebo groups respectively.
192
Probiotics were tried with 
an aim to prevent gut derived infection, but unexpectedly increased mortality leading to 
premature termination of the trial.
193
TNF-
α has been implicated as an important cytokine 
mediating systemic inflammation. In a proof of concept small study involving 28 patients 
with predicted severe AP, Pentoxifyllin, an oral TNF-
α antagonist, resulted in significantly 
fewer ICU admissions and shorter hospital stay.
194
A larger trial is currently in progress. 
Infliximab, a TNF-
α antagonist, is being tested in a RCT involving patients with AP of all 
grades of severity (
www.isrctn.com/ISRCTN16935761
).
Unmet needs and potential areas for future research:
Organ failure remains the proverbial Achilles heel of managing patients with severe AP. 
There is no specific therapy available either to treat or prevent the development of OF. The 
success of anticytokine therapy in chronic diseases such as inflammatory bowel disease, 
psoriasis and rheumatoid arthritis
195, 196
may not translate to AP. Future approaches include 
targeting intermediary signaling such as the increase in cytosolic calcium using ORAI1 
inhibitors
197
. The benefits of this approach remain to be seen in human AP, since ORAI1 is 
involved in innate immunity as well
198
. Similarly, NF-kB has been shown to play a critical 
role in AP 
199-201
. Pancreas-specific truncation of its trans-activating unit (RelA/p65) 
worsens pancreatic injury and lung inflammation. It would, therefore be important to know 
Garg and Singh
Page 12
Gastroenterology. Author manuscript; available in PMC 2020 May 01.
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whether clinically approved agents such as Bortezomib 
202
that interfere with NF-kB 
signaling affect the course of human AP. Some other exciting potential targets include UFAs, 
lipase, DAMPs, inflammasome, and kynurenine
203
, which remain to be tested in human 
studies.